1,2-dithiins having antifungal activity

Abstract

Novel 1,2-dithiin compounds useful as antifungal or anti-infective agents, as well as methods for their use as such, are described. The 1,2-dithiin compounds are particularly effective in treating infections, especially those caused by Candida albicans, Cryptococcus neoformans, Aspergillus fumigatus, Candida krusei, Candida parapsilosis, Candida tropicalis, Trichophyton rubrum, Epidermophyton species, Microsporum species, Sporothrix species, Blastomyces dermatitidis, Coccidiodes immiitis, Histoplasma capsulatum, Herpes virus, Influenza virus, Cytomegalovirus, human immunodeficiency virus, retrovirus, Adenovirus, Papillomavirus, Paravirus, Arenavirus, Bunyavirus, Coronavirus, Paramyxovirus, Picornavirus, Rhabdovirus, Togavirus, Hepadnavirus, Staphylococcus aureus, Streptococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, Enterobacter aerogenes, Klebsiella pneumoniae, Staphylococcus epidermis, Zanthomonus maltrophilia, Acinetobacter, Enterobacter cloacae, Serratia marscens, Listeria, Monocytogenes, Enterococcus faecalis, Streptococcus pyogenes; Streptococcus pneumonia, Viridans streptococci, Haemophilus influenzae, Proteus mirabills, Proteus vulgaris and Bacterioides fragilis.

What is claimed is: 
     
       1. A compound having the formula: ##STR39## and pharmaceutically acceptable salts thereof, wherein: R 2  and R 3  are hydrogen; G 1  and G 2  are independently selected from the group consisting of a C 1  -C 10  alkyl or branched alkyl group and a C 3  -C 10  cycloalkyl group;   R 1  is --OH;   R 4  is selected from the group consisting of, --OR 5 , --O(CO)R 5 , --SR 6  and a pyridone radical of the type: ##STR40## wherein R 7  is selected from the group consisting of hydrogen, --OH, --SH, --NO 2 , --NH 2 , halogen, trifluoromethyl, --CHO, --COOH, --COOR 8 , --OR 8  and SR 8  ;   A is nitrogen or carbon;   R 8  is an alkyl group of 1 to 6 carbon atoms;   R 5  and R 6  are independently selected from the group consisting of a C 1  -C 20  alkyl group, a C 1  -C 20  alkenyl group, a C 3  -C 10  cycloalkyl group and a radical of the type: ##STR41## said C 1  -C 20  alkyl and C 1  -C 20  alkenyl group being optionally substituted with one or more C 1  -C 20  alkyl groups;   X 1 , X 2 , X 3  and X 4  are independently 0-6;   R 9  is selected from the group consisting of hydrogen, a C 1  -C 6  alkyl group, a C 2  -C 6  alkenyl group, a C 2  -C 6  alkynyl group, halogen, trifluoromethyl, trichloromethyl, tribromomethyl, --NO 2 , --NH 2 , --OH, --SH, --CHO and --COOH;   R 10  is selected from the group consisting of hydrogen, a C 1  -C 6  alkyl group, a C 2  -C 6  alkenyl group, a C 2  -C 6  alkynyl group, halogen, trifluoromethyl, trichloromethyl, tribromomethyl, --NO 2 , --NH 2 , --OH, --SH, --CHO, --COOH, --NR 16  R 17 , --OR 18 , --SR 19 , --COOR 20 , phenyl, pyridyl, pyrazinyl, imidazolyl, pyrimidyl, triazyl, triazolyl, thiadiazolyl, tetrazolyl, thiazolyl, thiatriazolyl, pyrrolyl, furanyl, and thiopheneyl; said phenyl, pyridyl, pyrazinyl, imidazolyl, pyrimidyl, triazyl, triazolyl, thiadiazolyl, tetrazolyl, thiazolyl, thiatriazolyl, pyrrolyl, furanyl, and thiopheneyl groups being optionally substituted with one or more halogen, --OCH 3  or C 1  -C 6  alkyl groups;   R 11  is selected from the group consisting of hydrogen, a C 1  -C 6  alkyl group, a C 2  -C 6  alkenyl group, a C 2  -C 6  alkynyl group, halogen, trifluoromethyl, trichloromethyl, tribromomethyl, --NO 2 , --NH 2 , --OH, --SH, --CHO, --COOH, --NR 16  R 17 , --OR 18 , --SR 19 , --COOR 20 , phenyl, pyridyl, pyrazinyl, imidazolyl, pyrimidyl, triazyl, triazolyl, thiadiazolyl, tetrazolyl, thiazolyl, thiatriazolyl, pyrrolyl, furanyl, and thiopheneyl; said phenyl, pyridyl, pyrazinyl, imidazolyl, pyrimidyl, triazyl, triazolyl, thiadiazolyl, tetrazolyl, thiazolyl, thiatriazolyl, pyrrolyl, furanyl, and thiopheneyl groups being optionally substituted with one or more halogen, --OCH 3  or C 1  -C 6  alkyl groups;   R 12  is selected from the group consisting of hydrogen, a C 1  -C 6  alkyl group, a C 2  -C 6  alkenyl group, a C 2  -C 6  alkynyl group, halogen, trifluoromethyl, trichloromethyl, tribromomethyl, --NO 2 , --NH 2 , --OH, --SH, --CHO and --COOH;   R 13  is selected from the group consisting of hydrogen, a C 1  -C 6  alkyl group, a C 2  -C 6  alkenyl group, a C 2  -C 6  alkynyl group, halogen, trifluoromethyl, trichloromethyl, tribromomethyl, --NO 2 , --NH 2 , --OH, --SH, --CHO, --COOH, --NR 16  R 17 , --OR 18 , --SR 19 , --COOR 20 , phenyl, pyridyl, pyrazinyl, imidazolyl, pyrimidyl, triazyl, triazolyl, thiadiazolyl, tetrazolyl, thiazolyl, thiatriazolyl, pyrrolyl, furanyl, and thiopheneyl; said phenyl, pyridyl, pyrazinyl, imidazolyl, pyrimidyl, triazyl, triazolyl, thiadiazolyl, tetrazolyl, thiazolyl, thiatriazolyl, pyrrolyl, furanyl, and thiopheneyl groups being optionally substituted with one or more halogen, --OCH 3  or C 1  -C 6  alkyl groups;   R 14  is selected from the group consisting of hydrogen, a C 1  -C 6  alkyl group, a C 2  -C 6  alkenyl group, a C 2  -C 6  alkynyl group, halogen, trifluoromethyl, trichloromethyl, tribromomethyl, --NO 2 , --NH 2 , --OH, --SH, --CHO, --COOH, --NR 16  R 17 , --OR 18 , --SR 19 , --COOR 20 , phenyl, pyridyl, pyrazinyl, imidazolyl, pyrimidyl, triazyl, triazolyl, thiadiazolyl, tetrazolyl, thiazolyl, thiatriazolyl, pyrrolyl, furanyl, and thiopheneyl; said phenyl, pyridyl, pyrazinyl, imidazolyl, pyrimidyl, triazyl, triazolyl, thiadiazolyl, tetrazolyl, thiazolyl, thiatriazolyl, pyrrolyl, furanyl, and thiopheneyl groups being optionally substituted with one or more halogen, --OCH 3  or C 1  -C 6  alkyl groups;   R 15  is selected from the group consisting of hydrogen, a C 1  -C 6  alkyl group, a C 2  -C 6  alkenyl group, a C 2  -C 6  alkynyl group, halogen, trifluoromethyl, trichloromethyl, tribromomethyl, --NO 2 , --NH 2 , --OH, --SH, --CHO, --COOH, --COOR 25 , and phenyl; said phenyl being optionally substituted with one or more halogens, --OCH 3  or C 1  -C 6  alkyl groups;   R 16  and R 17  are independently a C 1  -C 6  alkyl group or form together a ring of 3 to 8 carbon atoms;   R 18  is selected from the group consisting of a C 1  -C 6  alkyl group, a C 2  -C 6  alkenyl group, a C 2  -C 6  alkynyl group, a C 3  -C 8  cycloalkyl group, a phenyl group, an alkyl acyl radical comprising 2 to 6 carbon atoms, and a phenyl acyl radical; said phenyl being optionally substituted with one or more halogens, --OCH 3  or C 1  -C 6  alkyl groups;   R 19  is selected from the group consisting of a C 1  -C 6  alkyl group, a C 2  -C 6  alkenyl group, a C 2  -C 6  alkynyl group, a C 3  -C 8  cycloalkyl group, a phenyl group, an alkyl acyl radical comprising 2 to 6 carbon atoms, and a phenyl acyl radical; said phenyl being optionally substituted with one or more halogens, --OCH 3  or C 1  -C 6  alkyl groups;   R 20  is selected from the group consisting of a C 1  -C 6  alkyl group, a C 2  -C 6  alkenyl group, a C 2  -C 6  alkynyl group, a C 3  -C 8  cycloalkyl group, a phenyl group, and a benzyl group; said phenyl and benzyl groups being optionally substituted with one or more halogens, --OCH 3  or C 1  -C 6  alkyl groups;   R 21  and R 22  are independently C 1  -C 6  alkyl groups or form together a ring of 3 to 8 carbon atoms;   R 23  is selected from the group consisting of a C 1  -C 6  alkyl group, a C 2  -C 6  alkenyl group, a C 2  -C 6  alkynyl group, a C 3  -C 8  cycloalkyl group, a phenyl group, an alkyl acyl radical comprising 2 to 6 carbon atoms, and a phenyl acyl radical; said phenyl being optionally substituted with one or more halogens, --OCH 3  or C 1  -C 6  alkyl groups;   R 24  is selected from the group consisting of a C 1  -C 6  alkyl group, a C 2  -C 6  alkenyl group, a C 2  -C 6  alkynyl group, a C 3  -C 8  cycloalkyl group, a phenyl group, an alkyl acyl radical comprising 2 to 6 carbon atoms, and a phenyl acyl radical; said phenyl being optionally substituted with one or more halogens, --OCH 3  or C 1  -C 6  alkyl groups;   R 25  is selected from the group consisting of a C 1  -C 6  alkyl group, a C 2  -C 6  alkenyl group, a C 2  -C 6  alkynyl group, a C 3  -C 8  cycloalkyl group, a phenyl group, and a benzyl group; said phenyl and benzyl groups being optionally substituted with one or more halogens, --OCH 3  or C 1  -C 6  alkyl groups;   B, C, D, and E are independently carbon or nitrogen;   F, G, H, and J are independently selected from the group consisting of carbon, nitrogen and sulfur, and   with the proviso that only one of either F, G, H, or J can be sulfur, and with the further proviso that if one of either F, G, H, or J is sulfur, then R 15  is hydrogen or x 4  =0.   
     
     
       2. A compound having the formula II: ##STR42## and pharmaceutically acceptable salts thereof, wherein: A is selected from the group consisting of --OAr, --O(CO)Ar, --NH(CO)Ar, --S--Ar and B; Ar is selected from the group consisting of phenyl, 1-imidazolyl, 2-imidazolyl, 3-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 2-quinoxalinyl, 3-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl, 7-quinoxalinyl, 8-quinoxalinyl and 5-tetrazolyl; said Ar being optionally substituted with one or more groups selected from the group consisting of phenyl, --OH, --OR, --COOH, --N(R)(R), --F, --Cl, --Br, --I, --CF 3 , --CCl 3 , --CBr 3 , --CI 3 , --NO 2 , a C 1  -C 10  alkyl group, a C 2  -C 10  alkenyl group, a C 2  -C 10  alkynyl group, --C(O)OC 1  -C 10  alkyl group, --C(O)OC 2  -C 10  alkenyl group, --C(O)OC 2  -C 10  alkynyl group and B;   each R is independently selected from the group consisting of H, a C 1  -C 10  alkyl group, a C 2  -C 10  alkenyl group and a C 2  -C 10  alkynyl group; and   B is a 5-7 membered saturated or unsaturated carbocyclic ring optionally having one or more heteroatoms selected from the group consisting of O, S and N; said B being optionally substituted with one or more groups selected from the group consisting of --OH, --OR, --COOH, --N(R)(R), --F, --Cl, --Br, --I, --CF 3 , --CCl 3 , --CBr 3 , --CI 3 , --NO 2 , a C 1  -C 10  alkyl group, a C 2  -C 10  alkenyl group, a C 2  -C 10  alkynyl group, --C(O)OC 1  -C 10  alkyl group, --C(O)OC 2  -C 10  alkenyl group, --C(O)OC 2  -C 10  alkynyl group and =O.   
     
     
       3. A compound selected from the group consisting of: 3-(hydroxymethyl)-6-[(phenyloxy)methyl]-1,2-dithiin;   3-(hydroxymethyl)-6-[(pyridyl-2-oxy)methyl]-1,2-dithiin;   3-(hydroxymethyl)-6-[(pyrid-2-one-1-yl)methyl]-1,2-dithiin;   3-(hydroxymethyl)-6-[(pyridyl-3-oxy)methyl]-1,2-dithiin;   3-(hydroxymethyl)-6-[(3-hydroxyphenyloxy)methyl]-1,2-dithiin;   3-(hydroxymethyl)-6-[[3-(N,N-dimethylamino)-phenyloxy]methyl]-1,2-dithiin;   3-(hydroxymethyl)-6-[(3-hydroxypyridazin-6-one-1-yl)methyl]-1,2-dithiin;   3-(hydroxymethyl)-6-[(3-hydroxypyridazine-6-oxy)methyl]-1,2-dithiin;   3-(hydroxymethyl)-6-[(2-trifluoromethylphenyloxy)methyl]-1,2-dithiin;   3-(hydroxymethyl)-6-[(2-fluorophenyloxy)methyl]-1,2-dithiin;   3-(hydroxymethyl)-6-[(5-nitropyridyl-2-oxy)methyl]-1,2-dithiin;   3-(hydroxymethyl)-6-[(5-nitropyrid-2-one-1-yl)methyl]-1,2-dithiin;   3-(hydroxymethyl)-6-[(3-ethynylphenyloxy)methyl]-1,2-dithiin;   3-(hydroxymethyl)-6-[methyloxy[methylbenzoate-3-yl]]-1,2-dithiin;   3-(hydroxymethyl)-6-[methyloxy[3-hydroxyquinoxalin-2-yl]]-1,2-dithiin;   3-(hydroxymethyl)-6-[(2-chloro-5-trifluoromethylphenyloxy)methyl]-1,2-dithiin;   3-(hydroxymethyl)-6-[methyloxy[methyl benzoate-4-yl]]-1,2-dithiin;   3-(hydroxymethyl)-6-[(2-hydroxy-3-fluorophenyloxy-1-yl)methyl]-1,2-dithiin;   3-(hydroxymethyl)-6-[(1-hydroxy-3-fluorophenyloxy-2-yl)methyl]-1,2-dithiin;   3-(hydroxymethyl)-6-[methylthio-[1-(4-hydroxyphenyl)tetrazol-5-yl]-1,2-dithiin;   3-(hydroxymethyl)-6-[[4-(imidazol-1-yl)phenyloxy]methyl]-1,2-dithiin;   3-(hydroxymethyl)-6-[[(2,2-dimethyl-1,3-dioxolan-4-yl)methyloxy]methyl]-1,2-dithiin;   3,6-bis{[(2,2-dimethyl-1,3-dioxolan-4-yl)methyloxy]methyl}-1,2-dithiin;   3-(hydroxymethyl)-6-[methyloxy(2,3-dihydroxypropane-1-yl)]-1,2-dithiin;   3-[[(2,2-dimethyl-1,3-dioxolan-4-yl)methyloxy]methyl]-6-[[methyloxy(2,3-dihydroxypropane-1-yl)]]-1,2-dithiin;   3-(hydroxymethyl)-6-[methyloxy[methyl benzoate-2-yl]]-1,2-dithiin; and   3-(benzoyloxymethyl)-6-(hydroxymethyl)-1,2-dithiin.   
     
     
       4. A method for inhibiting the growth of a pathogen, comprising contacting said pathogen with a compound according to claim 1, wherein said pathogen is selected from the group consisting of Candida albicans, Candida krusei, Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans, Aspergillus fumigatus, Trichophyton rubrum, Epidermophyton species, Microsporum species, Sporothrix species, Blastomyces dermatitidis, Coccidiodes immiitis, Histoplasma capsulatum, Herpes virus, Influenza virus, Cytomegalovirus, human immunodeficiency virus, retrovirus, Adenovirus, Papillomavirus, Paravirus, Arenavirus, Bunyavirus, Coronavirus, Paramyxovirus, Picornavirus, Rhabdovirus, Togavirus, Hepadnavirus, Staphylococcus aureus, Streptococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, Enterobacter aerogenes, Klebsiella pneumoniae, Staphylococcus epidermis, Zanthomonus maltrophilia, Acinetobacter, Enterobacter cloacae, Serratia marscens, Listeria, Monocytogenes, Enterococcus faecalis, Streptococcus pyogenes; Streptococcus pneumonia, Viridans streptococci, Haemophilus influenzae, Proteus mirabilis, Proteus vulgaris and Bacterioides fragilis. 
     
     
       5. A method for inhibiting the growth of a pathogen, comprising contacting said pathogen with a compound according to claim 2, wherein said pathogen is selected from the group consisting of Candida albicans, Candida krusei, Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans, Aspergillus fumigatus, Trichophyton rubrum, Epidermophyton species, Microsporum species, Sporothrix species, Blastomyces dermatitidis, Coccidiodes immiitis, Histoplasma capsulatum, Herpes virus, Influenza virus, Cytomegalovirus, human immunodeficiency virus, retrovirus, Adenovirus, Papillomavirus, Paravirus, Arenavirus, Bunyavirus, Coronavirus, Paramyxovirus, Picornavirus, Rhabdovirus, Togavirus, Hepadnavirus, Staphylococcus aureus, Streptococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, Enterobacter aerogenes, Klebsiella pneumoniae, Staphylococcus epidermis, Zanthomonus maltrophilia, Acinetobacter, Enterobacter cloacae, Serratia marscens, Listeria, Monocytogenes, Enterococcus faecalis, Streptococcus pyogenes; Streptococcus pneumonia, Viridans streptococci, Haemophilus influenzae, Proteus mirabills, Proteus vulgaris and Bacterioides fragilis. 
     
     
       6. A method for inhibiting the growth of a pathogen, comprising contacting said pathogen with a compound according to claim 3, wherein said pathogen is selected from the group consisting of Candida albicans, Candida krusei, Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans, Aspergillus fumigatus, Trichophyton rubrum, Epidermophyton species, Microsporum species, Sporothrix species, Blastomyces dermatitidis, Coccidiodes immiitis, Histoplasma capsulatum, Herpes virus, Influenza virus, Cytomegalovirus, human immunodeficiency virus, retrovirus, Adenovirus, Papillomavirus, Paravirus, Arenavirus, Bunyavirus, Coronavirus, Paramyxovirus, Picornavirus, Rhabdovirus, Togavirus, Hepadnavirus, Staphylococcus aureus, Streptococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, Enterobacter aerogenes, Klebsiella pneumoniae, Staphylococcus epidermis, Zanthomonus maltrophilia, Acinetobacter, Enterobacter cloacae, Serratia marscens, Listeria, Monocytogenes, Enterococcus faecalis, Streptococcus pyogenes; Streptococcus pneumonia, Viridans streptococci, Haemophilus influenzae, Proteus mirabilis, Proteus vulgaris and Bacterioides fragilis. 
     
     
       7. A pharmaceutical composition for use as an agent to inhibit the growth of a pathogen in warm-blooded animals, comprising a therapeutically effective amount of a compound of claim 1. 
     
     
       8. A pharmaceutical composition for use as an agent to inhibit the growth of a pathogen in warm-blooded animals, comprising a therapeutically effective amount of a compound of claim 2. 
     
     
       9. A pharmaceutical composition for use as an agent to inhibit the growth of a pathogen in warm-blooded animals, comprising a therapeutically effective amount of a compound of claim 3.